The pharmaceutical industry is constantly utilizing emerging technologies to produce the highest quality drug products obtainable. In order to ensure quality manufacturing of pharmaceutical products there is a necessity to provide an adequate level of sterility in the equipment and chemicals used. The development of isolation barriers, otherwise known as local controlled environments permits the manipulation of chemicals while maintaining a controlled sterile environment. The isolation barriers may be connected to a tank which can be used to store, mix, or process a sterile chemical or a mixture of sterile chemicals. The tank is typically a stainless steel pressure vessel and may be connected to the isolation barrier by a port which extends into the isolation barrier. The port has a cap that seals the tank during a steam sterilization cycle. Once the tank is sterilized, chemicals may be added to the tank through the connecting port via the isolation barrier.
Many problems and concerns have arisen in using the isolation barrier to maintain a sterile environment and assuring the sterility of all components used, particularly in a drug formulation process. To maintain sterility, both the tank and the isolation barrier require periodic sterilization to ensure that newly added chemicals do not become contaminated by residual chemicals or organisms used in a previous process. One method of maintaining sterility is to clean the tank and isolation barrier manually. However, this method of sterilization may not be validated in view of potential human error in ensuring that all areas the tank and isolation barrier are clean in accordance with federal requirements.
Another common sterility problem involves the use of an isolation barrier to add a sterile powder or a sterile liquid to an already sterile formulation. In this instance, the problem arises when a sterile mixture is introduced into the isolation barrier or tank and additional sterile chemicals need to be added. Before adding the additional chemicals, the isolation barrier requires sterilization. This involves sealing the tank with a cap to maintain the integrity of the tank and/or the sterile chemical mixture in the tank while sterilizing the isolation barrier. When using this method of sterilization, however, the sterility of the area directly under the cap cannot be certain. Hence, any newly added chemicals could be contaminated during this process.
Currently, both the tank and isolation barrier require different methods of sterilization, which the inventor has recognized as causing an additional problem with respect to adequate sterilization. The cap must be on the port leading into the isolation barrier during the steaming of the tank because the isolation barrier is not compatible with steam. The cap must also remain on during the sterilization of the isolation barrier because the tank is not compatible with chemicals used to sterilize the isolation barrier. Therefore, the area between the cap and port again remains unsterilized if these methods of sterilization are employed.
A variety of other sterilization methods have been proposed, however, all of these methods fail to provide adequate sterilization to the tank, the isolation barrier and any connecting valve structure. In particular, U.S. Pat. No. 4,146,570 to Nagy provides a sterilization apparatus and process wherein steam is generated within the apparatus for a specified time period and is released through an evacuating valve located at the bottom of the apparatus. Another prior art method of sterilization is disclosed in U.S. Pat. No. 5,268,144 to Heilmann, which discloses the use of a sterilizing medium which flows into a pressure-tight system for inserting medical devices requiring sterilization. U.S. Pat. No. 5,019,345 to Lorenz discloses a sterilization method which uses a valve structure that opens or closes based on the surrounding pressure or temperature to control the admission or drain of gas used during the sterilization process. Finally, U.S. Pat. No. 4,759,909 to Joslyn discloses a sterilization method comprising the steps of conditioning, steam sterilizing and drying goods placed in a sterilizing chamber. Although the above methods provide sterilization for a single sterile environment, none of these methods provides for different sterilization methods for multiple environments, such as a tank, an isolation barrier and a connecting valve structure when complete sterilization of the entire system is assured.
To ensure adequate sterilization of multiple environments, one proposal included the use of a ball valve between the tank and the isolation barrier. The use of a ball valve, however, created an additional problem due to the size of valve. A four inch ball valve, for example, has a body length of eight to twelve inches. This length creates a surface that is difficult to effectively clean and sterilize. The length also increases the distance from the top of the port to the interior of the tank.
U.S. Pat. No. 4,339,111 to Welch discloses a clean-in-place diaphragm valve having a cleaning fluid outlet used for circulating cleaning fluid through a valve chamber without having to remove the valve. This valve structure, however, is not designed to allow for the sterilization of the valve itself and the containers connected thereto. Therefore, there is no known convenient method of automatically sterilizing a tank, an isolation barrier and a connecting valve structure.
Until recently, the FDA required that drug formulations be performed in Class 100 clean rooms due to the inability to provide an adequate sterile environment. Such clean rooms, however, are expensive to maintain and are not particularly necessary in all drug formulation environments. Therefore, there is a need for an apparatus and method that provide adequate sterilization to multiple environments, that conform to government requirements and that provide a practical solution for the pharmaceutical industry.